Dendritic spines are the sites of most excitatory synapses in the brain. Changes in spine density and morphology are of significance for the formation of learning and memory, and spine dysfunction is an early event in the pathogenesis of Alzheimer's disease (AD) that likely directly contributes to cognitive dysfunctions. The Rho GEF kalirin has been shown to control dendritic spine morphogenesis via its activation of the small GTPase Rac. Rac in turn activates the p21-activated kinase, Pak, which in turn mediates actin cytoskeletal rearrangement and consequent changes in spine morphology. The recent development of the first kalirin KO mouse will be used to determine if the previously characterized kalirin- Rac and kalirin-GluR1 in vitro interactions are dysregulated in kalirin KO animals in vivo. Furthermore we will characterize the cognitive deficits of kalirin KO animals and determine the synaptic signaling deficits that mediate these deficits. Last, we will examine how kalirin loss affects synaptic structure and function in vivo. Because Alzheimer's disease (AD) is characterized by cognitive and dendritic spine deficits that closely parallel those induced by kalirin down-regulation, and because kalirin loss is a common feature of human Alzheimer's patients, understanding the role of kalirin in vivo is of extreme therapeutic relevance. Overall, the proposed aims will have enormous implications for understanding how dendritic spine dysfunctions affect learning a memory in vivo, an area of neuroscience is much is speculated, but little is known. In addition, because kalirin loss is evident in the forebrain of Alzheimer's patients, and because we present preliminary evidence indicating that kalirin loss is characteristic of a cellular Alzheimer's model, the characterization of the kalirin KO mouse may in conjunction with addition studies identify kalirin as a therapeutic target as has been suggested for the kalirin effector molecules Pak and GluR1. Lay Summary: Dendritic spines are sites of most excitatory synapses in the brain. By understanding how signaling molecules within dendritic spines affect spine density/morphology and how these molecules affect cognitive functions such as learning and memory, a better understanding how spine aberrations affect cognition will be determined. In addition, an understanding of the effects of synaptic dysfunction on cognition is of fundamental importance to more completely understanding the pathology of Alzheimer's disease.